ALI/ARDS is a non-specific inflammation of the lung secondary to various primary diseases, which can be divided into two categories: direct injury and indirect injury according to the nature of the injury. The main causes of direct injury are pneumonia and aspiration, while the causes of indirect injury are mainly systemic infections, trauma, etc., and can also be seen in various other diseases. Unfortunately, no drug therapy has been found to be completely effective for ALI/ARDS as confirmed by RCT. I. Local medication in the lung 1. Alveolar surface active substance supplementation therapy Pulmonary compliance decreases in ALI, and the function of alveolar surface active substance is weakened. In 1996, Auzueto et al. reported that the application of a protein-free alveolar surface active substance (Exosurf®, palmitoyl phosphate) was effective in 725 patients with ARDS due to systemic infection. A multicenter RCT applying a synthetic alveolar surface active substance (Venticule®) containing recombinant alveolar surface active protein C injected into the trachea of 448 patients with ARDS due to systemic infection found no decrease in 30-day survival.In 2003 Spragg et al. reported a large RCT applying a synthetic alveolar surface active substance (Venticule®) containing recombinant alveolar surface active protein C into the trachea of 448 patients with ARDS found that despite the safe use of the drug however, 28-day survival was not significantly reduced. In contrast, a medium-sized phase III clinical trial of alveolar surface active substance (Infasurf®) derived from calf alveolar lavage fluid applied to neonates, infants, and young ARDS patients found that the drug improved oxygenation status and reduced morbidity and mortality, and that a multicenter RCT of the composition, method of administration, dose, and duration of alveolar surface active substance is needed in the future. and from this Indications are that the drug is recommended for application at this time. 2, NO inhalation therapy inhalation concentration of 5~80ppm of NO can selectively diastolic pulmonary artery and correct pulmonary ventilation/blood flow ratio imbalance and improve oxygenation. What’s more, it is believed that it is expected to play a role in the treatment of right heart failure due to the decrease in pulmonary vascular resistance. Small studies in which intravenous application of almitrine bismesylate, a selective pulmonary vasoconstrictor, combined with inhaled NO improved these parameters in patients with ARDS have also been reported sporadically. However, large-scale phase II and III clinical trials have found no reduction in morbidity and mortality and duration of mechanical ventilation despite improved oxygenation with 5 ppm inhaled NO. Moreover, NO is not approved as a drug in Japan, so it cannot be used casually and requires the approval of the hospital ethics committee. In conclusion, NO is expected to improve oxygenation transiently and can be used as rescue therapy for intractable hypoxemia, but not as standard therapy for all ARDS patients. 3. Partial liquid ventilation (PLV), a biologically stable liquid with high affinity for oxygen called perfluorocarbon (PFC), has attracted attention as an alternative to blood. In the early days, PFC was often injected into the blood vessels, and later it was usually injected into the trachea for fluid exchange (i.e., the oxygenated PFC was repeatedly injected and drained into the trachea), and PLV, in which a portion of PFC is injected into the trachea and combined with conventional mechanical ventilation management, has been promoted clinically because it is easy, safe, and practical. A multicenter RCT on this therapy has been conducted since 1997, but its efficacy has not been confirmed. a multicenter RCT published in 2006 with 301 ARDS cases in 56 medical institutions suggested that the control group with a tidal volume of 10 ml/kg (107 cases), the small tidal volume PLV group with 10 ml/kg PFC (99 cases), and the large tidal volume PLV group with 20 ml/kg PFC The morbidity and mortality rates in the PLV group with large tidal volume of PFC (105 cases) were 15% 26,3% and 19,1%, respectively. The morbidity and mortality rates of PLV in both groups were higher than those in the control group, and the duration of mechanical ventilation was also prolonged, and the incidence of complications such as pneumothorax, hypoxemia and hypotension increased, suggesting that PLV was ineffective. 4. Other inhalation therapies prostaglandin E1 (PGE1) and prostaglandin I1 (PGI1) have been used in inhalation therapy because of their potent pulmonary vasodilatory effects, and have also been used in combination with NO inhalation therapy, but none of them had significant efficacy, and no multicenter RCT of inhalation therapy has been conducted. The study is based on the hypothesis that the prognosis is improved by actively removing extra-alveolar water from the lungs from an early stage, and that inhalation of the beta agonist promotes clearance. Glucocorticosteroids have long been thought to have a variety of effects such as anti-inflammatory and may inhibit inflammation and fibrosis to improve lung injury, and numerous clinical trials have been conducted. Several RCTs on high-dose hormone therapy for early ARDS were conducted in the latter half of the 1980s, but the prognosis of patients with ARDS was reported to be not improved, but rather the rate of death increased due to the increased chance of infection, so its efficacy was denied. These subjects also became an important basis for criticizing methylprednisolone 1,0g once every 6 hours for 4 times; high-dose hormone shock therapy with methylprednisolone 1,0g/d for 3 days as the basic framework is widely used in Japanese clinics. This therapy has not been confirmed by RCT, so it cannot be actively recommended, but its efficacy in ARDS due to fat embolism and Pneumocystis carinii pneumonia cannot be denied. On the other hand, Meduri et al. found that hormones are effective in fibrosis in advanced ARDS. meduri et al. applied 2 mg/kg of methylprednisolone for a long period of time (up to 32 days) after 7 days after onset of disease in ARDS patients with the aim of preventing fibrosis and then tapered the dose. Based on the results of this study, ARDS Net implemented a multicenter RCT with a total of 180 ARDS patients on methylprednisolone, but survival did not improve at 60 and 180 days, and the duration of mechanical ventilation was prolonged instead, making the efficacy of hormonal continuous therapy in advanced ARDS skeptical and not recommended at this time. The Surviving Systemic Infections Campaign (SSC) accepts the findings of Annane et al. and recommends 200 to 300 hydrocortisone for patients with systemic infections who have a negative ACTH stimulation test (Class C). However, the just-concluded, large-scale multicenter trial CORTICUS (Corticosteroid therapy of sepsis shock), which was conducted by the European Society of Critical Care Medicine, also failed to find its efficacy. 2. Antioxidants Antioxidants are expected to inhibit the activity of reactive oxygen species. From the perspective of the pathophysiology of ARDS, antioxidants have been used as potentially effective therapeutic agents. Some clinical reports have suggested that the imidazole antifungal drug ketoconazole, which has the effect of inhibiting thromboxane synthesis, has the potential to prevent the development of ARDS. Accordingly, ARDS Net conducted a large multicenter RCT expected to include 800 patients with ARDS, but observation of treatment outcomes in a staged 234 patients revealed no improvement in lung function or 28-day survival. The antioxidants N-acethylsysteine and procyteine were previously thought to be effective in ARDS, but no improvement in survival was found by a small RCT. Similarly, the antioxidant lisofylline, which was found to have an inhibitory effect on inflammatory cytokine expression in animal studies, was found to be ineffective in 235 patients with ARDS as a result of a large multicenter RCT by the ARDS Network in 1998. 3. Multiple enzyme inhibitors such as ustekin and gabexate mesylate are expected to reduce lung injury because they inhibit the release of neutrophil elastase from activated polymorphonuclear cells and have anticoagulant effects. These drugs have been widely used in Japan, and both animal studies and clinical experience suggest that they have inhibited acute lung injury, but there is no evidence of clinical efficacy without a multicenter RCT. In addition, there are some problems with these drugs in terms of the scope of medical insurance coverage, and appropriate countermeasures should be taken as soon as possible. On the other hand, sevelestat, a specific neutrophil elastase inhibitor, has been found to be effective in numerous animal studies, including post-administration. The mechanism of action of sevelestat is inhibition of neutrophil aggregation in the lung and destruction of lung tissue by neutrophil elastase, and therefore, a phase III RCT conducted in Japan found that efficacy such as shortening the duration of mechanical ventilation and ICU stay could be obtained. However, a multicenter RCT of 487 patients with ARDS conducted in Europe and the United States found that the sevelamerestat treatment group did not result in improvements in withdrawal days and morbidity and mortality rates. Because of the opposite results of these two large-scale RCTs, the drug is still being used only in Germany and Korea. A post-marketing follow-up of civelestat is now underway, but no consensus conclusion has been reached on whether civelestat improves the prognosis of patients with ARDS. 4. Anticoagulants have decreased blood concentrations of activated protein C in most patients with severe infections, and the prognosis is significantly correlated with their blood concentrations. This is due to the fact that inflammatory cytokines caused by systemic infections can inhibit the activation of protein C by thromboxane and others. Activated protein C is not only antithrombotic and promotes fibrinolysis, but also has a variety of functions, including anti-inflammatory. A large phase III multicenter RCT of recombinant activated protein C in up to 1,690 patients with severe infections in the United States found that continuous intravenous dosing of recombinant activated protein C for 96 hours reduced 28-day morbidity and mortality. At the time of initiation, 75% of all study subjects were mechanically ventilated, probably due to acute lung injury (the diagnosis of ALI/ARDS was not yet clear in this study), thus suggesting that activator protein C may also be effective in ARDS. Other agents such as antithrombin III agents, heparin, thromboxane, and tissue factor pathway inhibitors (TFPI) also seem to be expected to be effective by their mechanism of action, but their efficacy was not confirmed by the RCT, so they are not strongly recommended at this time. 5. Intravenous administration of prostaglandins intravenous application of the non-selective vasodilator PGE1 is expected to be of interest, but no significant efficacy has been found. The efficacy of intravenous application of PGE1 has been discredited in the second half of the 1980s. An RCT with the application of a microliposome (liposome-based) PGE1 preparation was found to yield a transient improvement in oxygenation but had no effect on long-term survival, and the trial was discontinued at 350 cases. A subsequent European multicenter RCT also concluded that it did not improve prognosis and therefore did not recommend intravenous PG. 6. Immunotherapy and other studies of systemic infections have been conducted with a variety of immunotherapies, but were discontinued as most were ineffective. Studies on immunotherapy for ALI/ARDS have not been conducted. In Japan, polymyxin B adsorption columns have been used clinically for the purpose of adsorbing endotoxin, but the efficacy of these columns for ARDS due to systemic infections is unknown. An overview of the main pharmacological therapies for ALI/ARDS has been given above. In Japan, the usual practice for pharmacotherapy of ALI/ARDS, including poor prognosis, is for clinicians to apply a large number of “drugs that may be effective despite uncertain efficacy” based on their own experience, and therefore these drugs need to be reexamined. In addition, it is necessary to differentiate these drugs into those that act directly on the lungs and those that treat systemic infections, and it is hoped that further research in this area will be conducted in the future.